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Category: genetics

Utility of Targeted RNA Analysis in Neurogenetic Disorders

Anti-CASPR2 encephalitis on EEG

Many patients show (DSWA) and IED, reflecting widespread cortical dysfunction.

Importantly, diffuse slowing and absence of deep (N3) sleep may signal a worse prognosis. — @Natalia Olaru.

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Objective The clinical manifestations of autoimmune encephalitis associated with contactin-associated protein-like 2 (CASPR2) were atypical and progressed slowly. We aimed to summarize the characteristics of video-electroencephalography (V-EEG) and video-polysomnography (V-PSG) to achieve early recognition and assess long-term outcomes.

Abstract: The changing landscape of urothelial carcinoma: on the edge of paradigm shift

In this Review Joshua J. Meeks discusses advancements in biomarkers and novel therapeutics that are likely to dramatically improve survival of patients with Bladder Cancer.

1Departments of Urology and.

2Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

3Jesse Brown VA Medical Center, Department of Veterans Affairs, Chicago, Illinois, USA.

Address correspondence to: Joshua J. Meeks, Department of Urology, Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. Phone: 312.695.8146; Email: joshua.meeks@northwestern.edu.

Challenges and opportunities in adapting high-throughput functional assays for in vivo neuroscience

High-throughput functional assays such as CRISPR screens and massively parallel reporter assays have transformed studies of gene regulation in cultured cells, but their translation to neuroscience remains limited.

The brain presents unique barriers to scaling these assays, including delivery bottlenecks, low recovery, and the complexity of cellular diversity and spatial architecture.

Emerging strategies—ranging from optimized viral vectors and streamlined library design to integration with singlecell and spatial transcriptomics—offer paths to overcome these limitations.

Together, these innovations are paving the way toward in vivo functional genomics approaches that can bridge the gap between genetic variation, regulatory logic, and brain function. sciencenewshighlights ScienceMission https://sciencemission.com/high-throughput-functional-assays

Genetic sequencing has aided in the discovery of novel mutations in inborn errors of immunity, but their clinical relevance often remains unclear

In this Research Article, Marcus Altfeld & team identify a TLR8 gene mutation causing immune overactivation and inflammation in two siblings, linking genetic change to immune system dysfunction and disease: Immunology.

14 Hamburg Center for Translational Immunology;

15 German Center for Child and Adolescent Health (DZKJ), partner site Hamburg; and.

16 Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Structures of hantavirus glycoprotein tetramers

This surface protein complex for the Andes virus is a mushroom-shaped structure called a Gn-Gc tetramer. To map the 3D structures, the team first produced virus-like particles that mimic a real virus, but without the genome that makes a virus infectious. They then used a cryo-electron microscope—which shines an electron beam through a frozen sample and detects the shadows created by molecules—to reconstruct the three-dimensional structures of the Gn-Gc tetramers on the surface of the virus-like particles.

But there was a twist: To obtain extremely high-resolution structures, the researchers painstakingly identified and isolated shadows from only the tetramers that were pointing sidewise relative to the electron beam and ignored those pointing in other directions. This allowed them to borrow a reconstruction method typically used on individual proteins.

The resulting structures have an extremely high resolution of 2.3 angstroms, meaning details the size of just a couple of atoms were effectively captured. That’s enough to represent a transformational improvement over another team’s model of the tetramer from a few years ago, at a resolution of 12 angstroms, still tiny but large enough to produce some key inaccuracies – ones effectively corrected with the newer method and resulting structure.

These latest structures show the Gn-Gc tetramer in a particular state before it has infected a cell. For vaccines or antibody therapies to be most effective against a hantavirus, mimicking surface proteins at this pre-infection stage is essential. ScienceMission sciencenewshighlights.

Hantaviruses, transmitted from rodents to people, have a death rate approaching 40%. They’re found around the world, and because there are no approved vaccines or treatments, they’re among the pathogens of highest concern for future pandemics. They made news in the United States last year when Betsy Arakawa, the wife of actor Gene Hackman, died from a hantavirus infection in New Mexico in March.

New findings published in the journal Cell about the Andes virus, a hantavirus endemic to the southwestern U.S. and other parts of North and South America, represent a crucial first step towards much-needed vaccines and antibody therapies for this and other hantaviruses.

Continue reading “Structures of hantavirus glycoprotein tetramers” | >

MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights

Hereditary spastic paraplegia refers to a group of disorders characterized by progressive spasticity of lower extremities. The Genetic Nomenclature Study Group found differing frequency of variant types across 3 HSP genes: ATL1, SPAST and REEP1.

The PubMed literature search and articles obtained through additional sources yielded a total of 239 articles for HSP–ATL1, of which 70 were eligible, 531 articles for HSP–SPAST, for which 187 were eligible, and 334 articles for HSP–REEP1, of which 31 were eligible (Fig. 1, Supplementary File_HSP Article Screening Log).

By classifying these articles according to study type, we found that the most common were genetic screening studies (36.3%), family studies (30.4%), followed by, case reports/series (23.2%), and other/mixed-type studies (10.0%). While genetic screening studies were the most common study type for HSP–SPAST and HSP–REEP1, family studies were the most common study type for HSP–ATL1 (Table S2).

A new class of Alzheimer’s biomarkers: Why protein shape may beat protein levels

Researchers have identified a new type of blood-based biomarker test for Alzheimer’s disease that measures structural changes in proteins, providing more information on the underlying biology of the disease than standard blood tests. The findings, published in Nature Aging, also provide new insights into how Alzheimer’s disease biology may differ between males and females.

“This work introduces a fundamentally new, blood-based approach to detecting and staging Alzheimer’s disease,” said Dr. Richard Hodes, director of NIH’s National Institute on Aging (NIA). “By revealing protein structural changes associated with genetic risk, symptom severity, and sex differences—features not captured by existing biomarkers—this research could enable earlier diagnosis and more effective clinical trials.”

Genomic reorganization at the transition to gametogenesis

Using a technique called Hi-C analysis, which looks at how DNA is arranged in three dimensions inside the nucleus, the team found that at this transitional point the genome’s three-dimensional organisation becomes less structured and chromosomes become more separated inside the nucleus.

Creating sperm and eggs in the laboratory (in vitro) remains one of the greatest challenges in reproductive biology. To study this process, scientists use primordial germ cell–like cells (PGCLCs), which are lab-generated cells derived from embryonic stem cells that mimic the embryo’s earliest reproductive cells. However, these PCGLCs often fail to complete all the steps of meiosis, making it difficult to create functional sperm and eggs in petri dishes.

After studying the process in germ cells from the embryos, the team studied lab-generated mouse PCGLCs to see if the centromeres migrated to the periphery of the nucleus in vitro too, but they did not see the same phenomenon.

“The presence of this chromosome conformation in embryonic germ cells, but not lab-grown cells, suggests that this structural change could be required for meiosis to proceed properly, and could explain why meiosis is so difficult to recreate outside the body,” says the author, “but we need to do more work to fully characterise the process before we can say for sure.”

“Our study has uncovered a previously unknown and frankly very surprising restructuring of genome architecture that occurs in developing germ cells, which we believe is critical for a successful execution of meiosis,” says the senior author. ScienceMission sciencenewshighlights.

In our cells, our DNA carries chemical or ‘epigenetic’ marks that decide how genes will be used in different tissues. Yet in the group of specialised cells, known as ‘germ cells’, which will later form sperm and eggs, these inherited chemical instructions must be erased or reshuffled so development can begin again with a fresh blueprint in future generations.

Continue reading “Genomic reorganization at the transition to gametogenesis” | >

Size-shifting nanoparticles successfully deliver mRNA medicine to the pancreas

In recent years, mRNA in lipid nanoparticles (mRNA–LNPs) has emerged as a promising strategy for treating numerous conditions, including COVID-19, various cancers and chronic genetic disorders. To date, this technology has not been successfully used for pancreatic diseases, but that could be about to change. In a paper published in Nature, scientists from China report the development of a new lipid nanoparticle drug-delivery system specifically designed for the pancreas.

Lipid nanoparticles are a special class of fat-based carriers that encapsulate and deliver nucleic acids such as messenger RNA into cells. Among the reasons they have not worked for the pancreas until now is that most LNPs naturally accumulate in the liver and spleen. That means the therapeutic molecules they carry can’t accumulate to high enough levels to be beneficial.

However, the research team realized that while the liver and spleen are wrapped in a dense, protective outer layer called a capsule, the pancreas is only covered by a thin layer of connective tissue. They wondered if these organ capsules act as a biological filter. If so, they could perhaps design nanoparticles large enough to be physically blocked by the walls of the spleen and liver, leaving the pancreas as the only place to go. They named this discovery the capsule-filter-mediated pancreatic-targeted (CAMP) mechanism.

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